Background:Thyroid cancer is one of the fastest growing cancer diagnoses in the United States. Non-medullary thyroid cancer accounts for 95% of all thyroid cancer cases. Up to 8% of all non-medullary thyroid cancers are hereditary. Familial non-medullary thyroid cancer (FNMTC) is more aggressive than sporadic disease. No susceptibility gene for FNMTC has been identified. The best approach for screening at risk family members for FNMTC is unknown. This protocol is designed to determine the natural history and best screening strategy for FNMTC, and to identify susceptibility gene(s) for FNMTC. Summary:This is a prospective study of individuals with or at risk for non-medullary thyroid cancer. Individuals will be studied over time within the context of their families in order to quantify prospective risks of cancers in family members, to establish the natural history of FNMTC, define the spectrum of diseases within the families, to identify precursor states, to try to assess the contribution of genetic and environmental components of risk, and to develop effective screening strategies. We have performed several genomic studies in tumor and germline DNA from familial and sporadic cases of non-medullary thyroid cancer. MicroRNA profiling of the sporadic and familial tumors matched for age and stage of cancer show distinctly different patterns of deregulated microRNA as compared to normal thyroid tissue. Also, we have found that cases of familial non-medullary thyroid cancer as compared to unaffected family members, sporadic thyroid cancer cases and healthy volunteer have short telomere length in their germline DNA. We have excluded that genes/proteins, which determine telomere length, account for the difference observed in telomere length between affected and unaffected family members. From our whole-exome sequencing studies in kindreds with familial non-medullary thyroid cancer, we have identified candidate susceptibility genes which we are currently validating in additional families and performing functional genomic studies to determine their role in tumor cell biology.